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United States Patent |
5,256,692
|
Gordon
,   et al.
|
October 26, 1993
|
Sulfur-containing HMG-COA reductase inhibitors
Abstract
Novel sulfur-containing compounds which inhibit the activity of
3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, having a
sulfur-containing side-chain bonded to a hydrophobic anchor group through
an acetylenic or ethylenic linkage. Pharmaceutical compositions, and
methods of use for the treatment or prevention of hypercholesterolemia,
atheroschlerosis, hyperlipoproteinaemia and hyperlipidemia are provided,
as are novel methods for preparation and intermediate compounds.
Inventors:
|
Gordon; Eric M. (Pennington, NJ);
Pluscec; Jelka (Trenton, NJ)
|
Assignee:
|
E. R. Squibb & Sons, Inc. (Princeton, NJ)
|
Appl. No.:
|
817875 |
Filed:
|
January 7, 1992 |
Current U.S. Class: |
514/532; 514/570; 546/223; 548/323.5; 548/547; 560/11; 560/15; 562/426; 562/429 |
Intern'l Class: |
A01N 037/10; C07C 317/00 |
Field of Search: |
562/429,426
560/15,11
514/532,570
|
References Cited
U.S. Patent Documents
4062973 | Dec., 1977 | Nickl et al. | 514/532.
|
4191776 | Mar., 1980 | Nickl et al. | 514/532.
|
5001128 | Mar., 1991 | Neuenschwander et al. | 514/570.
|
5025000 | Jun., 1991 | Karanewsky et al. | 514/80.
|
5025017 | Jun., 1991 | Karanewsky et al. | 514/277.
|
5049577 | Sep., 1991 | Varma et al. | 514/409.
|
5049578 | Sep., 1991 | Varma et al. | 514/409.
|
5089523 | Feb., 1992 | Varma et al. | 514/460.
|
5091378 | Feb., 1992 | Karanewsky et al. | 514/80.
|
5099035 | Mar., 1992 | Saunders et al. | 549/292.
|
Foreign Patent Documents |
0127848 | Dec., 1984 | EP.
| |
2205838 | Dec., 1988 | GB.
| |
PCT8603488 | Jun., 1986 | WO.
| |
Primary Examiner: Dees; Jose G.
Assistant Examiner: Jones; Dwayne C.
Attorney, Agent or Firm: Kilcoyne; John M.
Claims
What is claimed is:
1. A compound having the following formula I or II:
##STR58##
where: n is 0, 1 or 2;
R is hydrogen or lower alkyl;
Z is a substituted or unsubstituted biphenyl group; and
R.sup.1 is hydrogen, alkyl or aryl; or a salt thereof.
2. A compound of claim 1, wherein said salt is a pharmaceutically
acceptable salt.
3. A compound of claim 1, wherein the chiral center
##STR59##
of the sulfur-containing side chain of said compound is of the same
absolute configuration corresponding to when R=hydrogen and --OH is of the
S configuration.
4. A compound of claim 1 of the formula I or a salt thereof.
5. A compound of claim 1, where R is hydrogen.
6. A compound of claim 1, where R.sup.1 is hydrogen or an alkali metal
cation.
7. A compound of claim 1, where Z is a lipophilic anchor group which is
capable of binding to a hydrophobic part of HMG-CoA reductase not utilized
in binding HMG-CoA.
8. A compound of claim 1 wherein Z is selected from a substituted or
unsubstituted biphenyl where
##STR60##
a is 1, 2, 3, or 4 and each R.sup.76 substituent is independently selected
from
(i) hydrogen,
(ii) alkyl,
(iii) aryl,
(iv) aralkyl,
(v) aralkoxy,
(vi) heterocyclo,
(vii) cycloalkyl,
(viii) alkoxy,
(ix) alkenyl,
(x) cycolalkenyl,
(xi) halogen,
(xii) hydroxy,
(xiii) amino,
(xiv) alkylamino, or
(xv) dialkylamino; and
b is 1, 2, 3, 4, or 5 and each R.sup.77 substituent is independently
selected form those groups (i) to (xv) described above for R.sup.76.
9. A compound selected from the group consisting of:
(S)-4-[[[4'-fluoro-3,3',5-trimethyl[1,1'-biphenyl]-2-yl]ethynyl]thio]-3-hyd
roxybutanoic acid, methyl ester;
(S)-4-[[[4'-fluoro-3,3',5-trimethyl[1,1'-biphenyl]-2-yl]ethynyl]thio]-3-hyd
roxybutanoic acid;
(S)-4-[[[4'-fluoro-3,3',5-trimethyl[1,1'-biphenyl]-2-yl]ethynyl]sulfonyl]-3
-hydroxybutanoic acid; and
(S)
4-[[[4'-fluoro-3,3',5-trimethyl[1,1'-biphenyl]-2-yl]ethynyl]sulfinyl]-3-hy
droxybutanoic acid.
10. A hypocholesterolemic composition comprising an amount of said compound
of claim 1 effective therefor, and a pharmaceutically acceptable vehicle
or diluent.
11. A hypolipidemic composition comprising an amount of said compound of
claim 1 effective therefor, and a pharmaceutically acceptable vehicle or
diluent.
12. A hypoliproteinaemic composition comprising an amount of said compound
of claim 1 effective therefor, and a pharmaceutically acceptable vehicle
or diluent.
13. An antiatheroschlerotic composition comprising an amount of said
compound of claim 1 effective therefor, and a pharmaceutically acceptable
vehicle or diluent.
Description
FIELD OF THE INVENTION
The present invention relates to new sulfur-containing compounds which
inhibit the activity of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)
reductase and thus are useful in inhibiting cholesterol biosynthesis, to
pharmaceutical compositions containing such compounds, to methods for
preparing, and new intermediates formed in the preparation of such
compounds, and to methods of using such compounds.
SUMMARY OF THE INVENTION
The instant invention provides compounds having a sulfur-containing group,
which group preferably binds to the HMG binding domain of HMG-CoA
reductase, linked by an acetylenic or ethylenic linkage to a hydrophobic
group, which group is preferably a lipophilic anchor group capable of
binding to a hydrophobic part of HMG-CoA reductase not utilized in binding
HMG-CoA. The compounds of the instant invention are inhibitors of the
enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase)
and are thus inhibitors of cholesterol biosynthesis (hypocholesterolemic
agents). The instant invention therefore provides a method and
pharmaceutical compositions for reducing or maintaining plasma cholesterol
levels. The instant invention also provides methods and pharmaceutical
compositions for the treatment and/or prevention of atheroschlerosis,
hyperlipodemia, and hyperlipoproteinaemia.
The inventive compounds are advantageous in that they are readily
synthesized by the novel methods also provided by the instant invention.
Further provided are the novel intermediates produced in the preparation
of the inventive compounds.
DETAILED DESCRIPTION OF THE INVENTION
Compounds are provided having the following formulae I or II:
##STR1##
where n is zero, 1 or 2;
R is hydrogen or lower alkyl;
Z is a hydrophobic group, preferably a lipophilic anchor group which is
capable of binding to a hydrophobic part of HMG-CoA reductase not utilized
in binding HMG-CoA; and
R.sup.1 is
(i) hydrogen,
(ii) alkyl,
(iii) aryl,
(iv) the group
##STR2##
where R.sup.2 is hydrogen, alkyl or aryl and R.sup.3 is alkyl or aryl, or
(v) if not already covered above, a group forming, together with the atoms
to which it is bonded, an ester group which is hydrolyzable in vivo;
and salts, preferably pharmaceutically acceptable salts, thereof. Reference
to a compound or salt herein is defined to include solvates such as
hydrates thereof, unless otherwise indicated.
The group
##STR3##
of the compounds of formulae I and II preferably is capable of binding to
the HMG binding domain of HMG-CoA reductase. The capability of binding to
the HMG binding domain of HMG-CoA reductase may be indicated, for example,
by the ability of a compound to inhibit the activity of that enzyme. With
respect to the group Z, the capability of binding to a hydrophobic part of
HMG-CoA reductase not utilized in binding HMG-CoA may be indicated, for
example, by an enhanced potency of the compound containing that group in
inhibiting the activity of HMG-CoA reductase relative to the activity
exhibited by the corresponding compound in which Z is hydrogen.
The group R is preferably hydrogen.
The group R.sup.1 is preferably hydrogen or a salt cation, especially an
alkali metal cation. When R.sup.1 is the group
##STR4##
is preferably hydrogen or lower alkyl and R.sup.3 is preferably lower
alkyl.
Compounds of the formula I or salts thereof are preferred. With respect to
formula II, such as where R is hydrogen, compounds or salts thereof where
Z is, for example, not phenylmethylene, naphthylmethylene or a moiety
bonded to the group --CH.dbd.CH-- (cis or trans) through a phenylmethylene
or naphthylmethylene group may be prepared.
The hydrophobic anchor group Z is preferably an aryl, cycloalkyl,
2,2-diarylalkenyl or heterocyclo group. Exemplary Z groups include the
following groups (i) to (xxiii):
##STR5##
where one of R.sup.4 and R.sup.5 is substituted phenyl and the other of
R.sup.4 and R.sup.5 is lower alkyl; R.sup.7 and R.sup.6 together are
--(CH.dbd.CH).sub.2 -- or --(CH.sub.2).sub.4 -- and are joined to complete
a six membered carbocyclic ring;
##STR6##
an exemplary group (vi) being the following group (vi)(a):
##STR7##
wherein R.sup.11, R.sup.12, R.sup.13 and R.sup.14 are the same or
different and are each independently selected from hydrogen, halogen,
lower alkyl (such as lower haloalkyl), phenyl, substituted phenyl or
OR.sup.29 (wherein R.sup.29 is hydrogen, alkanoyl, benzoyl, phenyl,
substituted phenyl such as halophenyl, phenyl-lower alkyl, alkyl such as
haloalkyl, cinnamyl, allyl, cycloalkyl-lower alkyl, adamantyl-lower alkyl
or substituted phenyl-lower alkyl), and where a dotted line denotes an
optional double bond;
where Z is (vi), R.sup.19 and R.sup.20 are the same or different and are
hydrogen, lower alkyl or OH; R.sup.17 is lower
##STR8##
or aryl(CH.sub.2)--; R.sup.18 is lower alkyl, hydroxy, oxo or halogen, q
is 0, 1, 2 or 3; and R.sup.30 is hydrogen, alkyl, cycloalkyl, aryl or
aralkyl;
where Z is (ii), (v), (vii), (viii), (ix), (x), or (xi), one of R.sup.7 and
##STR9##
and the other is lower alkyl, cycloalkyl or phenyl--(CH.sub.2).sub.p --; p
is 0, 1, 2, 3 or 4; R.sup.31 is hydrogen, lower alkyl, lower alkoxy
(preferably other than t-butoxy), halogen, phenoxy or benzyloxy; R.sup.32
is hydrogen, lower alkyl, lower alkoxy, halogen, phenoxy or benzyloxy;
R.sup.33 is hydrogen, lower alkyl, lower alkoxy, or halogen (and,
preferably, with the provisos that both R.sup.32 and R.sup.33 are hydrogen
when R.sup.31 is hydrogen, R.sup.33 is hydrogen when R.sup.32 is hydrogen,
not more than one of R.sup.31 and R.sup.32 is trifluoromethyl, not more
than one of R.sup.31 and R.sup.32 is phenoxy and not more than one of
R.sup.31 and R.sup.32 is benzyloxy); R.sup.15 is hydrogen, C.sub.1-4
alkyl, C.sub.3-6 cycloalkyl, C.sub.1-4 alkoxy (preferably other than
t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, R.sup.16
is hydrogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, trifluoromethyl, fluoro,
chloro, phenoxy or benzyloxy (and, preferably, with the provisos that
R.sup.16 is hydrogen when R.sup.15 is hydrogen, not more than one of
R.sup.15 and R.sup.16 is trifluoromethyl, not more than one of R.sup.15
and R.sup.16 is phenoxy, and not more than one of R.sup.15 and R.sup.16 is
benzyloxy); R.sup.21 and R.sup.22 are independently selected from
hydrogen, alkyl, cycloalkyl, adamantyl-1 or
##STR10##
where R.sup.31, and R.sup.33 are as defined above and q is 0, 1, 2, 3 or
4; and Y is O, S or N--R.sup.21 ;
where Z is (xii), R.sup.24 is hydrogen or primary or secondary C.sub.1-6
alkyl; R.sup.25 is primary or secondary C.sub.1-6 alkyl; or R.sup.24
+R.sup.25 is (CH.sub.2).sub.r or (cis)CH.sub.2 --CH.dbd.CH--CH.sub.2 ;
r=2, 3, 4, 5 or 6; R is lower alkyl, cycloalkyl or
##STR11##
wherein R.sup.15, R.sup.16, R.sup.31, R.sup.32 and R.sup.33 are as defined
above;
where Z is (ii), R.sup.10 and R.sup.9 are both H, Cl, Br, CN, CF.sub.3,
phenyl, 1-4C alkyl, 2-8C alkoxycarbonyl, --CH.sub.2 OR.sup.34 or
--CH.sub.2 OCONHR.sup.35, R.sup.34 is H or 1-6C alkanoyl; R.sup.35 is
alkyl or phenyl optionally substituted by F, Cl, Br or 1-4C alkyl; or
R.sup.10 and R.sup.9 taken together are --(CH.sub.2).sub.s --, --CH.sub.2
OCH.sub.2 --, --CON(R.sup.36)CO--, or --CON(R.sup.37)N(R.sup.38)CO--; s=3
or 4; R.sup.36 =H, 1-6C alkyl, phenyl or benzyl; R.sup.37 and R.sup.38 are
H, 1-4C alkyl or benzyl;
where Z is (xiii), R.sup.28 is lower alkyl, cycloalkyl, adamantyl-1 or
##STR12##
t=1, 2, 3 or 4; R.sup.26 and R.sup.27 are the same or different and are
each independently selected from hydrogen, lower alkyl, lower alkoxyl
(preferably other than t-butoxy), halogen, phenoxy or benzyloxy (and,
preferably, with the provisos that R.sup.27 must be hydrogen when R.sup.26
is hydrogen, not more than one of R.sup.26 and R.sup.27 is
trifluoromethyl, not more than one and R.sup.26 and R.sup.27 is phenoxy,
and not more than one of R.sup.26 and R.sup.27 is benzyloxy);
##STR13##
where R.sup.39 and R.sup.40 are the same or different and are each
independently selected from
(i) hydrogen,
(ii) alkyl,
(iii) aryl,
(iv) cycloalkyl,
(v) aralkyl,
(vi) aralkoxy,
(vii) alkenyl,
(viii)cycloalkenyl, and
(ix) heterocyclo;
R.sup.41 is selected from
(i) hydrogen,
(ii) lower alkyl,
(iii) aryl,
(iv) cycloalkyl,
(v) alkoxy,
(vi) aralkyl,
(vii) aralkoxy,
(viii)alkenyl,
(ix) cycloalkenyl,
(x) halo-substituted alkyl,
(xi) adamantyl, and
(xii) heterocyclo;
R.sup.42 is selected from
(i) hydrogen,
(ii) lower alkyl,
(iii) aryl,
(iv) cycloalkyl,
(v) alkoxy,
(vi) aralkyl,
(vii) aralkoxy,
(viii)alkenyl,
(ix) cycloalkenyl,
(x) adamantyl,
(xi) halogen,
(xii) halo-substituted alkyl, and
(xiii)heterocyclo;
or R.sup.41 and R.sup.42 taken together can be
##STR14##
--(CH.dbd.CH).sub.2 --; n is 0 or 1;
p is 3, 4 or 5;
q is 0, 1, 2, or 3; and
r is 0, 1, 2, or 3;
##STR15##
R.sup.43 is aryl or alkyl; R.sup.44 and R.sup.45 are the same or different
and are hydrogen, lower alkyl or aryl; or R.sup.44 and R.sup.45 taken
together form a cycloalkyl group;
##STR16##
R.sup.46 is hydrogen, lower alkyl, aryl, lower alkoxy, cycloalkyl,
heterocyclo, aralkyl, or heterocycloalkyl;
R.sup.47 is lower alkyl, cycloalkyl or aralkyl;
A is O or NR.sup.48, wherein R.sup.48 is hydrogen or lower alkyl;
##STR17##
R.sup.49 is hydrogen, alkyl, alkenyl, aryl, alkylaryl, one of R.sup.50 and
R.sup.51 is hydrogen, and the other is hydrogen, alkyl, alkenyl, aryl, or
alkylaryl; or and R.sup.50 and R.sup.51 are both lower alkyl; or
R.sup.50 and R.sup.51 together complete a hydrocarbon ring that is
cycloalkyl or cycloalkenyl;
a 5-pyrazolopyridinyl group, or a moiety containing, and bonded through, a
5-pyrazolopyridinyl group such as:
##STR18##
where R.sup.56, R.sup.57, R.sup.58 and R.sup.59 are independently (i)
hydrogen
(ii) alkyl,
(iii) aryl,
(iv) aralkyl,
(v) aralkoxy,
(vi) heterocyclo,
(vii) cycloalkyl,
(viii) alkoxy,
(ix) alkenyl,
(x) cycloalkenyl,
(xi) halogen,
(xii) hydroxy,
(xiii) amino,
(xiv) alkylamino, or
(xv) dialkylamino;
a 5-pyrimidinyl group, or a moiety containing, and bonded through, a
5-pyrimidinyl group such as:
##STR19##
where R.sup.60, R.sup.61 and R.sup.62 are independently (i) hydrogen,
(ii) alkyl,
(iii) aryl,
(iv) aralkyl,
(v) aralkoxy,
(vi) heterocyclo,
(vii) cycloalkyl,
(viii) alkoxy,
(ix) alkenyl,
(x) cycloalkenyl, or
(xi) halogen;
##STR20##
where R.sup.63 and R.sup.64 are each independently fluoro or hydrogen,
except that at least one of R.sup.63 and R.sup.64 is fluoro;
R.sup.65 is hydrogen, alkyl, cycloalkyl, aryl, or arylalkyl;
and wherein carbons 5 to 6 are single- or double-bonded and carbons 6 to 7
are single- or double-bonded, except that carbons 5 to 6 and 6 to 7 are
not both double-bonded;
##STR21##
where R.sup.66 is hydrogen or --S(O).sub.m --R.sup.68 and R.sup.67 is
hydrogen or S(O).sub.n --R.sup.69, except that R.sup.66 and R.sup.67 are
not both hydrogen, or one of R.sup.66 and R.sup.67 is --S-alkylene-SH and
the other is hydrogen;
R.sup.68 and R.sup.69 are each independently hydrogen, acyl, alkyl,
alkenyl, alkynyl, aryl, aralkyl,
##STR22##
alkoxycarbonylalkylene or trifluoromethyl or R.sup.68 and R.sup.69
together are alkylene of 1 to 6 carbon atoms;
A.sub.1 and A.sub.2 are each independently hydrogen, alkyl, or alkaryl;
m is 0, 1, or 2; and
n is 0, 1 or 2;
##STR23##
where R.sup.70 and R.sup.71 are the same or different and are hydrogen,
lower alkyl or aryl;
A.sub.3 is
##STR24##
or a single bond, R.sup.75 is lower alkyl; R.sup.72 is lower alkyl or
aryl; R.sup.73 and R.sup.74 are the same or different and are hydrogen or
lower alkyl; and, particularly,
##STR25##
where a is 1, 2, 3 or 4 and each R.sup.76 substituent is independently
selected from
(i) hydrogen,
(ii) alkyl,
(iii) aryl,
(iv) aralkyl,
(v) aralkoxy,
(vi) heterocyclo,
(vii) cycloalkyl,
(viii) alkoxy,
(ix) alkenyl,
(x) cycloalkenyl,
(xi) halogen,
(xii) hydroxy,
(xiii) amino,
(xiv) alkylamino, or
(xv) dialkylamino; and
b is 1, 2, 3, 4 or 5 and each R.sup.77 substituent is independently
selected from those groups (i) to (xv) described above for R.sup.76.
The above exemplary groups Z are described, for example, in (a) U.S. Pat.
No. 5,724,453, issued Jun. 23, 1992 to Karanewsky (group (i)); (b) U.S.
Pat. No. 5,091,378, issued Feb. 25, 1992 to Karanewsky et al. Ser. No.
07/182,710, filed Apr. 18, 1988 (groups (ii) to (xiii)); (c) U.S.
application Ser. No. 07/588,800, filed Sep. 27, 1990 to Robl (group
(xiv)); (d) U.S. Pat. No. 5,049,578, issued Sep. 17, 1991 to Varma et al.
(group (xv)); (e) U.S. Pat. No. 5,189,180, issued Feb. 23, 1993 to
Karanewsky filed May 1, 1991 (group (xvi)); (f) U.S. Pat. No. 5,197,104,
issued Jan. 5, 1993 to Varma et al. (group (vi)(a)); (g) U.S. Pat. No.
5,049,577, issued Sep. 17, 1991 to Varma et al. (group (xvii)); (h) U.S.
application Ser. No. 07/754,886, filed Sep. 4, 1991 to Robl (group
(xviii)); (i) U.S. Pat. No. 5,202,327, issued Apr. 13, 1993 to Robl (group
(xix)); (j) U.S. Pat. No. 5,089,523, issued Feb. 18, 1992 to Varma et al.
Ser. No. 521,880, filed May 11, 1990 (group (xx)); (k) U.S. application
Ser. No. 07/724,272, filed Jul. 1, 1991 to Varma et al. (group (xxi)); and
(l) U.S. Pat. No. 5,106,992, issued Apr. 21, 1992 to Magnin et al.; all of
the above documents ((a) through (l)) incorporated herein by reference.
The term "alkyl" as employed herein alone or as part of another group
preferably denotes both straight and branched chain hydrocarbons
containing 1 to 12 carbons in the normal chain, preferably 1 to 7 carbons,
such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl,
pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,
2,2,4-trimethyl-pentyl, nonyl, decyl, undecyl, dodecyl, the various
branched chain isomers thereof, and the like as well as such groups
including one or more halo-substituents, (e.g. F, Br, Cl or I, or
CF.sub.3), for example, trihalomethyl, alkoxy substituents, aryl
substituents, alkyl-aryl substituents, haloaryl substituents, cycloalkyl
substituents, alkyl-cycloalkyl substituents, hydroxy substituents,
alkylamino substituents, alkanoylamino substituents, arylcarbonylamino
substituents, nitro substituents, cyano substituents, thiol substituents
or alkylthio substituents. The term "lower alkyl" as employed herein
preferably denotes such alkyl groups as described above containing 1 to 6
carbon atoms in the normal chain.
The term "alkenyl" as employed herein alone or as part of another group
preferably denotes such groups as described above for alkyl, further
containing at least one carbon to carbon double bond.
The term "alkynyl" as employed herein alone or as part of another group
preferably denotes such groups described above for alkyl, further
containing at least one carbon to carbon triple bond.
The term "cycloalkyl" as employed herein alone or as part of another group
preferably denotes saturated cyclic hydrocarbon groups containing one to
three rings and 3 to 12 ring carbons, preferably 3 to 8 ring carbons,
which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, and adamantyl, any of
which groups may be substituted, for example, with 1 or 2 halogens, 1 or 2
lower alkyl groups, 1 or 2 lower alkoxy groups, 1 or 2 hydroxy groups, 1
or 2 alkylamino groups, 1 or 2 alkanoylamino groups, 1 or 2
arylcarbonylamino groups, 1 or 2 amino groups, 1 or 2 nitro groups, 1 or 2
cyano groups, 1 or 2 thiol groups, and/or 1 or 2 alkylthio groups.
The term "cycloalkenyl" as employed herein alone or as part of another
group preferably denotes such groups as described above for cycloalkyl,
further containing at least one carbon to carbon double bond in the ring
system.
The term "acyl" as employed herein refers to all organic moieties which may
be derived from an organic carboxylic acid by removal of the hydroxyl
group.
The term "aryl" as employed herein preferably denotes monocyclic or
bicyclic substituted or unsubstituted aromatic groups containing from 6 to
12 carbons in the ring portion, such as phenyl, biphenyl, naphthyl,
substituted phenyl, substituted biphenyl or substituted naphthyl wherein
the substituent may be 1, 2 or 3 alkyl, preferably lower alkyl, groups,
halogen(s) (e.g., Cl, Br or F), 1, 2 or 3 alkoxy, preferably lower alkoxy,
groups, 1, 2 or 3 hydroxy groups, 1, 2 or 3 phenyl groups, 1, 2 or 3
phenoxy groups, 1, 2 or 3 alkanoyloxy groups, 1, 2 or 3 benzoyloxy groups,
1, 2 or 3 haloalkyl groups, 1, 2 or 3 haloalkoxy groups, 1, 2 or 3
halophenyl groups, 1, 2 or 3 allyl groups, 1, 2 or 3 cycloalkyl groups, 1,
2 or 3 cycloalkylalkyl groups, 1, 2 or 3 alkylamino groups, 1, 2 or 3
dialkylamino groups, 1, 2 or 3 alkanoylamino groups, 1, 2 or 3
arylcarbonylamino groups, 1, 2 or 3 amino groups, 1, 2 or 3 nitro groups,
1, 2 or 3 cyano groups, 1, 2 or 3 thiol groups, 1, 2 or 3 (alkyl).sub.3
silyloxy or (phenyl).sub.2 (alkyl)silyloxy groups, methylenedioxy where
the methylene group may be substituted by 1 or 2 lower alkyl groups, 1, 2
or 3 arylalkenyl groups, and/or 1, 2 or 3 alkylthio groups.
The terms "aralkyl", "aryl-alkyl" or "aryl-lower alkyl" as used herein
alone or as part of another group refer to alkyl or lower alkyl groups as
discussed above having an aryl substituent, such as benzyl.
The terms "lower alkoxy", "alkoxy", or "aryloxy" or "aralkoxy" as employed
herein alone or as part of another group include any of the above lower
alkyl, alkyl, aryl or aralkyl groups linked to an oxygen atom.
The terms "lower alkylthio", "alkylthio", "arylthio", or "aralkylthio" as
employed herein alone or as part of another group include any of the above
lower alkyl, alkyl, aryl or aralkyl groups linked to a sulfur atom.
The terms "lower alkylamino", "alkylamino", "arylamino", or
"arylalkylamino" as employed herein alone or as part of another group
include any of the above lower alkyl, alkyl, aryl or arylalkyl groups
linked to a nitrogen atom.
The term "alkanoyl" as used herein alone or as part of another group refers
to an alkyl group linked to a carbonyl group.
The term "halogen" or "halo" as used herein refers to chlorine, bromine,
fluorine, and iodine, with chlorine or fluorine being preferred.
The term "heterocyclo" preferably denotes fully saturated or unsaturated,
monocyclic or bicyclic, aromatic or nonaromatic hydrocarbon groups having
5 or 6 atoms in each ring and at least one heteroatom in at least one
ring. The heterocyclo group has 1 or 2 oxygen atoms, 1 or 2 sulfur atoms,
and/or 1 to 4 nitrogen atoms in the ring. The heterocyclo group may be
substituted with halogen(s), 1, 2 or 3 lower alkoxy groups, 1, 2, or 3
aralkyl groups, 1, 2 or 3 hydroxy groups, 1, 2 or 3 phenyl groups, 1, 2 or
3 alkanoyloxy groups, 1, 2 or 3 benzoyloxy groups, 1, 2 or 3 halophenyl
groups, 1, 2 or 3 alkyl groups, 1, 2 or 3 alkylamino groups, 1, 2 or 3
alkanoylamino groups, 1, 2 or 3 arylcarbonylamino groups, 1, 2 or 3 amino
groups, 1, 2 or 3 nitro groups, 1, 2 or 3 cyano groups, and 1, 2 or 3
thiol groups. Exemplary heterocyclo groups are 2- and 3-thienyl, 2- and
3-furyl, 2- and 3-pyrrolyl, 2-, 3- and 4-pyridyl, 2-, 4- and 5-imidazolyl,
2- and 3-pyrrolidinyl, 2-, 3- and 4-piperidinyl, 2-, 3- and 4-azepinyl,
4-, 5-, 6- or 7-indolyl, 4-, 5-, 6- or 7-isoindolyl, 5-, 6-, 7- or
8-quinolinyl, 5-, 6-, 7- or 8-isoquinolinyl, 4-, 5-, 6- or
7-benzothiazolyl, 4-, 5-, 6- or 7-benzoxazolyl, 4-, 5-, 6- or
7-benzimidazolyl, 4-, 5-, 6- or 7-benzoxadiazolyl, and 4-, 5-, 6- or
7-benzofurazanyl.
The term "salt(s)" refers to acidic and/or basic salts formed with
inorganic and organic acids and bases. Basic salts are preferred.
Exemplary basic salts include ammonium salts such as alkylammonium salts,
alkali metal salts such as lithium, sodium and potassium salts (which are
preferred), alkaline earth metal salts such as calcium and magnesium
salts, salts with organic bases, for example, amine salts such as
dicyclohexylamine salt, benzathine, N-methyl-D-glucamine, hydrabamine
salts, salts with amino acids such as arginine and lysine and equivalent
such salts. The nontoxic, pharmaceutically acceptable salts are preferred,
although other salts are also useful, for example, in isolation or
purification steps which may be employed during preparation.
All stereoisomers of the compounds of the instant invention are
contemplated, either in admixture or in pure or substantially pure form.
Compounds of the formulae I or II or salts thereof where n is 1 may be
prepared as one or both of the two diastereoisomers which may be formed
(based on the position of the groups attached to the sulfinyl group). For
all compounds of the formulae I or II or salts thereof (that is, where n
is 0, 1 or 2), the chiral center
##STR26##
of the sulfur-containing side chain is preferably of the same absolute
configuration corresponding to that where R=hydrogen and the group --OH is
of the S configuration.
The compounds of the instant invention may, for example, be in the free or
solvate, such as hydrate form, and may be obtained by the following novel
methods of the invention.
##STR27##
Compounds of the formula I where n is zero may be prepared as shown above
in Reaction Scheme I.
Reaction Scheme I begins by reacting a compound (a) with a compound (b) to
produce a compound of the formula III, where R.sub.a.sup.1 is R.sup.1 as
defined for the formula I except that R.sub.a.sup.1 may not be hydrogen,
Pro is a protecting group which may be cleaved in subsequent steps without
the destruction of the remainder of the molecule, and is preferably
--Si(t-butyl)(diphenyl), L is a leaving group such as mesylate, tosylate,
triflate or, especially, a halogen, most preferably iodo, R* is
heterocyclo such as heteroaromatic, or alkyl, alkenyl, cycloalkyl,
cycloalkenyl, or, preferably, aryl such as benzyl, particularly
p-methylbenzyl, and M is an alkali metal such as potassium.
Compounds of the formula (a) are known and may be prepared by the skilled
artisan. Compounds of the formula (b) may also be prepared by the skilled
artisan as discussed following. For example, a compound of the formula (b)
having the preferred iodo leaving group L may be prepared starting with
the following bromide:
##STR28##
where the above bromide may itself be prepared by employing procedures
analogous to those described in Acta. Chem. Scand., B., 1983, 37, 341-344.
The bromide may be dissolved in solution in dimethylformamide (DMF) with
imidazole and 4-dimethylamino pyridine, and the resulting solution treated
with the halide of the protecting group "Pro", e.g. with t-butyldiphenyl
silyl chloride, under an inert atmosphere such as argon to form the
following protected ether:
##STR29##
A solution of the above protected ether in an inert organic solvent such as
methyl ethyl ketone or DMF may be treated with sodium iodide under an
inert atmosphere such as argon, to form iodide compound (b).
The reaction of compounds (a) and (b) is preferably conducted at a
temperature of from about 0.degree. C. to about 100.degree. C., most
preferably from about 50.degree. C. to about 75.degree. C.; and preferably
at a pressure of from about 1 atm to about 5 atm. The reaction is
preferably completed over the course of about 1 hour to about 24 hours,
and is preferably conducted under an atmosphere of nitrogen or argon.
Molar ratios of compound (a) to compound (b) are preferably from about 1:1
to about 10:1, particularly from about 1:1 to about 3:1. Solvents are
preferably employed which are selected from organic or inorganic solvents
such as acetonitrile or dimethylsulfoxide (DMSO), most preferably
dimethylformamide. Amounts of solvents are preferably those where the
compound (b) starting material is from about 1 to about 5% by weight,
based on the combined weight of solvent and compound (b).
The above reaction method, and the compounds of the formula III produced,
are novel.
The compound of formula III is then contacted with a compound (c) and a
metallating agent, yielding the compound of formula IV. Preferably, the
compound (c) is pre-contacted with the metallating agent to form a
metallated anion of the compound (c) prior to contact with the formula III
compound. Preferred metallating agents are organic lithium compounds such
as t-butyl and n-butyl lithium.
Compounds of the formula (c) may be obtained according to methods such as
those described in the patents and patent applications (a) through (1)
recited above and incorporated herein by reference.
The reaction involving the compound of formula III and the compound (c) is
preferably conducted at a temperature of from about -100.degree. C. to
about 40.degree. C., most preferably from about -78.degree. C. to about
0.degree. C.; and preferably at a pressure of from about 1 atm to about 5
atm. The reaction is preferably completed over the course of about 1 hour
to about 24 hours, and is preferably conducted under an atmosphere of
inert gas such as argon.
Molar ratios of compound (c) to the compound of formula III are preferably
from about 1:1 to about 1:5, particularly from about 1:1 to about 1:2.
Solvents are preferably employed which are selected from dry organic
solvents such as acetonitrile or dimethylformamide (DMF), most preferably
tetrahydrofuran. Amounts of solvents are preferably those where the
formula III starting material is from about 1 to about 5% by weight, based
on the combined weight of solvent and formula III compound.
The same conditions, for example, temperature, solvent employed and the
like, as described above for contacting the compound (c) with the compound
of formula III are preferably employed for precontacting the formula (c)
compound and metallating agent to form the metallated anion of the formula
(c) compound. Molar ratios of metallating agent to compound (c) are
preferably those from about 1:1 to about 1:3, particularly those from
about 1:1 to about 1:1.5.
The above reaction method and compounds of the formula IV are novel.
The group "Pro" of the compound of the formula IV may then be cleaved to
form a compound of the formula I. For example, when --O--(Pro) is a silyl
ether, cleavage may be effected by treating the formula IV compound with a
cleaving agent such as acetic acid and tetrabutylammonium fluoride, or
with HCl or other inorganic acids.
The cleavage is preferably conducted at a temperature of from about
-50.degree. C. to about +50.degree. C., most preferably from about
0.degree. C. to about 30.degree. C.; and preferably at a pressure of from
about 1 atm to about 5 atm. Cleavage is preferably completed over the
course of about 1 hour to about 24 hours, and is preferably conducted
under an atmosphere of nitrogen or argon.
Molar ratios of cleaving agent to the compound of the formula IV are
preferably from about 1:1 to about 1:10, particularly from about 1:2 to
about 1:5. Solvents are preferably employed which are selected from dry
organic solvents such as acetonitrile or dimethylformamide, most
preferably tetrahydrofuran. Amounts of solvents are preferably those where
the formula IV starting material is from about 1 to about 5% by weight,
based on the combined weight of solvent and formula IV compound.
The cleavage method, producing the inventive compounds of the formula I
where n is zero, is novel.
Compounds of the formula I having the ester group R.sub.a.sup.1 may
optionally be hydrolyzed. Hydrolysis may be conducted, for example, by
treatment with a strong base such as lithium hydroxide or sodium hydroxide
in the presence of dioxane, methanol, acetonitrile, tetrahydrofuran or
other inert organic solvent under an inert atmosphere such as argon,
preferably at a temperature of from about room temperature to about
80.degree. C. A molar ratio of base:ester of from about 1:1 to about 1.1:1
is preferred. The basic salt formed may then be treated with a strong acid
such as HCl to form the corresponding acid.
Hydrolysis, producing the inventive compounds of the formula I, is novel.
##STR30##
Compounds of the formula I where n is zero, prepared as in Reaction Scheme
I above, may be employed in Reaction Scheme II for the preparation of
compounds of the formula I where n is 1.
According to Reaction Scheme II, a compound of the formula I having the
thio group --S-- is contacted with an oxidizing agent capable of
transforming the thio group to a sulfinyl group
##STR31##
Exemplary oxidizing agents capable of such transformation include
m-chloroperbenzoic acid, peracetic acid in a chlorinated hydrocarbon
solvent such as methylene chloride, chloroform, 1,2-dichloroethane or the
like, (n-butyl).sub.4 N.sup.+ IO.sub.4.sup.- in refluxing chloroform or
hydrogen peroxide, particularly an alkali metal metaperiodate such as
sodium metaperiodate.
The oxidation is preferably conducted at a temperature of from about
0.degree. C. to about 50.degree. C.; most preferably from about 20.degree.
C. to about 30.degree. C.; and preferably at a pressure of from about 1
atm to about 5 atm. The reaction is preferably completed over the course
of about 1 hour to about 24 hours, and is preferably conducted under an
atmosphere of inert gas such as argon.
Molar ratios of oxidizing agent to the starting compound of the formula I
(n=0) are preferably about 1:1. Solvents are preferably employed which are
selected from organic or inorganic solvents such as methylene chloride or
acetic acid, most preferably a mixture of methanol and water. Amounts of
the solvent are preferably those where the formula I starting material is
from about 1 to about 5% by weight, based on the combined weight of
solvent and formula I compound.
The oxidizing method is novel.
##STR32##
Compounds of the formula I where n is zero prepared as in Reaction Scheme I
above, or compounds of the formula I where n is 1 prepared as in Reaction
Scheme II above, may be employed in Reaction Scheme III for the
preparation of compounds of the formula I where n is 2.
According to Reaction Scheme III, a compound of the formula I having the
thio group --S-- or the sulfinyl group
##STR33##
is contacted with an oxidizing agent capable of transforming the thio or
sulfinyl group to a sulfonyl group
##STR34##
Exemplary oxidizing agents capable of such transformation include those
recited for Reaction Scheme II. m-Chloroperoxybenzoic acid is preferred as
the oxidizing agent.
The oxidation is preferably conducted at a temperature of from about
-50.degree. C. to about 50.degree. C.; most preferably from about
20.degree. C. to about 30.degree. C.; and preferably at a pressure of from
about 1 atm to about 5 atm. The reaction is preferably completed over the
course of about 1 hour to about 24 hours, and is preferably conducted
under an atmosphere of nitrogen.
Molar ratios of oxidizing agent to the compound of formula I where n=zero
are preferably from about 2:1 to about 10:1, particularly from about 4:1
to about 6:1. Molar ratios of oxidizing agent to the compound of formula I
where n=1 are preferably from about 1:1 to about 10:1, particularly from
about 4:1 to about 6:1. Solvents are preferably employed which are
selected from organic solvents such as methylene chloride, most preferably
trichloromethane. Amounts of solvents are preferably those where the
formula I starting material is from about 1 to about 5% by weight, based
on the combined weight of solvent and formula I compound.
The oxidation method is novel.
##STR35##
Compounds of the formula II where n is zero may be prepared as shown in
Reaction Scheme IV. Reaction Scheme IV begins by reacting a compound of
the formula III, prepared as in Reaction Scheme I above, with a compound
(d), that is, the metallated anion of the compound Z--CH.dbd.CH.sub.2, to
produce a compound of the formula V. The compound of formula (d) may be
prepared by the following procedure, beginning with the aldehyde:
Z--CHO.
The above aldehyde may be obtained according to methods such as those
described in the patents and patent applications (a) through (1) recited
above and incorporated herein by reference. Reaction of the aldehyde with
tetrabromomethane in the presence of triphenylphosphine and a dry, inert
organic solvent such as dichloromethane at low (for example, -10.degree.
C.) temperatures produces the dibromovinyl compound
--CH.dbd.C(Br).sub.2.
The above dibromovinyl compound may be dehalogenated by contact with tin
hydride (SnH.sub.4) to produce the bromovinyl compound
Z--CH.dbd.CHBr.
The above bromovinyl compound may then be converted directly to the
compound (d) by contact with a metallating agent, thereby forming the
metallated anion of the compound Z--CH.dbd.CH.sub.2. Preferred metallating
agents are organic lithium compounds such as t-butyl and n-butyl lithium.
The reaction involving the compound of formula III and the compound (d) is
preferably conducted at a temperature of from about -100.degree. C. to
about 50.degree. C., most preferably from about -78.degree. C. to about
0.degree. C.; and preferably at a pressure of from about 1 atm to about 5
atm. The reaction is preferably completed over the course of about 1 hour
to about 24 hours, and is preferably conducted under an atmosphere of
nitrogen or argon.
Molar ratios of compound (d) to the compound of formula III are preferably
from about 1:1 to about 1:3, particularly from about 1:1 to about 1:2.
Solvents are preferably employed which are selected from inorganic and
organic solvents such as tetrahydrofuran or ethyl ether. Amounts of
solvents are preferably those where the formula III starting material is
from about 1 to about 5% by weight, based on the combined weight of
solvent and formula III compound.
Compounds of the formula V, prepared as above, contain both the cis and
trans stereoisomeric forms. These stereoisomers may be separated, or may
be retained as a mixture in the subsequent procedures of Reaction Scheme
IV. Deprotection, and optional hydrolysis, of compounds of the formula V
to produce compounds of the formula II may be achieved by the methods
described above for the compounds of the formula I.
Compounds of the formula V are novel, as is the method described herein for
preparation of these compounds. Also novel are the methods to deprotect
and, optionally, hydrolyze compounds of the formula V to prepare the
compounds of the formula II.
##STR36##
Compounds of the formula II where n is zero, prepared as in Reaction Scheme
IV above, may be employed in Reaction Scheme V for the preparation of
compounds of the formula II where n is 1.
According to Reaction Scheme V, a compound of the formula II having the
thio group --S-- is contacted with an oxidizing agent capable of
transforming the thio group to a sulfinyl group
##STR37##
Exemplary oxidizing agents capable of such transformation include those
recited for Reaction Scheme II, particularly an alkali metal metaperiodate
such as sodium metaperiodate.
The oxidation is preferably conducted at a temperature of from about
-50.degree. C. to about +50.degree. C.; most preferably from about
0.degree. C. to about 30.degree. C.; and preferablY at a pressure of from
about 1 atm to about 5 atm. The reaction is preferably completed over the
course of about 1 hour to about 24 hours, and is preferably conducted
under an atmosphere of inert gas such as argon.
Molar ratios of oxidizing agent to the starting compound of the formula II
(n=0) are preferably about 1:1. Solvents are preferably employed which are
selected from organic or inorganic solvents such as chloroform or
methylene chloride, most preferably a mixture of methanol and water.
Amounts of the solvent are preferably those where the formula II starting
material is from about 1 to about 5% by weight, based on the combined
weight of solvent and formula II compound.
The oxidizing method is novel.
##STR38##
Compounds of the formula II where n is zero prepared as in Reaction Scheme
IV above, or compounds of the formula II where n is 1 prepared as in
Reaction Scheme V above, may be employed in Reaction Scheme VI for the
preparation of compounds of the formula II where n is 2.
According to Reaction Scheme VI, a compound of the formula II having the
thio group --S-- or the sulfinyl group
##STR39##
is contacted with an oxidizing agent capable of transforming the thio or
sulfinyl group to a sulfonyl group
##STR40##
Exemplary oxidizing agents capable of such transformation include those
recited for Reaction Scheme II. m-Chloroperoxybenzoic acid is preferred as
the oxidizing agent.
The oxidation is preferably conducted at a temperature of from about
0.degree. C. to about 100.degree. C.; most preferably from about
30.degree. C. to about 50.degree. C.; and preferably at a pressure of from
about 1 atm to about 5 atm. The reaction is preferably completed over the
course of about 1 hour to about 24 hours.
Molar ratios of oxidizing agent to the compound of formula II where n=zero
are preferably from about 2:1 to about 10:1, particularly from about 4:1
to about 6:1. Molar ratios of oxidizing agent to the compound of formula
II where n=1 are preferably from about 1:1 to about 10:1, particularly
from about 4:1 to about 6:1. Solvents are preferably employed which are
selected from organic solvents such as methanol or methylene chloride,
most preferably trichloromethane. Amounts of solvents are preferably those
where the formula II starting material is from about 1 to about 5% by
weight, based on the combined weight of solvent and formula II compound
The oxidation method is novel.
The instant invention thus provides novel intermediates and methods of
preparation which are described in the above Reaction Schemes. These novel
intermediates include those compounds designated above as III, IV, and V,
including all stereoisomers, salts and solvates thereof. Salts (and
solvates by definition) thereof may be employed in, or prepared by, the
novel methods of preparation wherever compounds of the formulae III, IV or
V are employed or prepared.
The compounds of the invention may be prepared as racemic mixtures which
may later be resolved, for example, to obtain the 3-S-isomer which is
preferred. Preferably, optically active compounds of the invention are
prepared directly by using chiral intermediates of the desired
stereoisomeric configuration in the methods set forth in the above
Reaction Schemes.
The compounds of the instant invention are inhibitors of
3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and thus are
useful in inhibiting cholesterol biosynthesis. The activity of the instant
compounds therefor may be demonstrated by any of the tests set forth in
British Patent No. 2,205,838, incorporated herein by reference. Generally,
compound selectivity favoring greater inhibitory activity in hepatic
tissue is an attribute for a cholesterol synthesis inhibitor.
The instant invention also provides pharmaceutical compositions comprising
at least one of the inventive compounds in association with a
pharmaceutically acceptable vehicle or diluent. The pharmaceutical
composition may be formulated employing conventional solid or liquid
vehicles or diluents, as well as pharmaceutical additives of a type
appropriate to the mode of desired administration. The compounds may, for
example, be administered by an oral route, such as in the form of tablets,
capsules, granules or powders, or they may be administered by a parenteral
route in the form of injectable preparations. Such dosage forms preferably
contain from about 1 to 2000 mg of active compound per dosage. The dose to
be administered depends on the unitary dose, the symptoms, and the age and
the body weight of the patient, and may be determined by the skilled
artisan. Exemplary pharmaceutical compositions of the instant invention
are hypocholesterolemic, hypolipoproteinaemic, antiatheroschlerotic and/or
hypolipidemic compositions comprising an amount of the inventive compound
effective therefor.
The inventive compounds may be administered in a similar manner as known
compounds suggested for use in inhibiting cholesterol biosynthesis, such
as lovastatin, particularly to subjects which are mammalian species such
as humans, dogs, cats and the like. Thus, the compounds of the invention
may be administered in an amount from about 1 to 2000 mg in a single dose
or in the form of individual doses from 1 to 4 times per day, preferably 4
to 200 mg in divided dosages of 1 to 100 mg, suitably 0.5 to 50 mg 2 to 4
times daily or in sustained release form.
The instant invention also provides methods for the treatment or prevention
of hypercholesterolemia, atheroschlerosis, hyperlipoproteinaemia, and/or
hyperlipidemia comprising the step of administering to a subject in need
thereof an inventive compound in an amount effective therefor.
The following working Examples represent preferred embodiments of the
present invention, and are not intended to limit the scope or spirit of
the instant claims.
EXAMPLE 1
Preparation of
(S)-4-[[[4'-Fluoro-3,3',5-trimethyl[1,1'-biphenyl]-2-yl]ethynyl]-thio]-3-h
ydroxybutanoic acid, methyl ester
(a) 2,3,4-Trihydroxybutanoic acid, hydrated calcium salt
##STR41##
Calcium carbonate (50 g) was added to a solution of D-isoascorbic acid
(44.0 g, 250 mM) in H.sub.2 O (625 ml), and the suspension cooled to
0.degree. C. (ice bath) and treated portionwise with 30% H.sub.2 O.sub.2
(100 ml). The mixture was stirred at 30.degree.-40.degree. C. (oil bath)
for 30 minutes. Darco (10 g) was added and the black suspension heated on
a steam bath until evolution of O.sub.2 ceased. The suspension was
filtered through Celite, evaporated in vacuo (bath temperature 40.degree.
C.), taken up in H.sub.2 O (50 ml), transferred to a large beaker and
warmed on a steam bath. CH.sub.3 OH was added until the solution was
turbid and the beaker set aside in the fridge overnight. The gummy
precipitated solid was collected by filtration, air dried overnight and
ground in a mortar and pestle to give 30.836 g (75.2%) of the triol title
product as a powdery white hydrated calcium salt with consistent C.sup. 13
NMR spectral data. TLC (7:2:1) isopropanol-NH.sub.4 OH--H.sub.2 O,
Rf=0.19, PMA.
(b) 2,4-Dibromo-3-hydroxy butanoic acid, methyl ester
##STR42##
The triol obtained in step (a) above (30 g) was stirred in 30-32% HBr in
acetic acid (210 ml) for 24 hours under Drierite. Methanol (990 ml) was
then added to the brown solution and it was stirred overnight under
Drierite. The mixture was evaporated to an orange oil, taken up in
CH.sub.3 OH (75 ml), refluxed for 2.0 hours, evaporated, partitioned
between ethyl acetate (100 ml) and H.sub.2 O, the organic phase washed
with H.sub.2 O (2.times.) and brine, then dried over anhydrous Na.sub.2
SO.sub.4 and evaporated to give 22.83 g (90.5%) of the dibromide title
product as a light orange oil with consistent C.sup.13 NMR spectral data.
TLC (1:1) ethyl acetate-hexane, Rf=0.69, UV & PMA.
(c) (S)-4-Bromo-3-hydroxybutanoic acid, methyl ester
##STR43##
An argon purged solution of the dibromide obtained in step (b) above (20.8
g, 75.4 mM) and anhydrous sodium acetate (NaOAc) (21.0 g) in ethyl acetate
(370 ml) and glacial acetic acid (37 ml) was treated with 5% Pd/C (1.30 g)
and the black suspension stirred under one atmosphere of H.sub.2 while
monitoring uptake (22.4 l/mole). After 2.0 hours H.sub.2 uptake was
complete, the mixture was filtered through Celite, the filtrate washed
with saturated NaHCO.sub.3 and brine and then dried over anhydrous
MgSO.sub.4 and evaporated to give the crude bromoester title product as a
brown oil. The crude oil was combined with another batch (starting from
36.77 g of the dibromide) and vacuum distilled to give 25.771 g (61.3%) of
the pure bromoester title product as a clear oil with
b.p.=79.degree.-80.degree. C. (1.0 mm Hg) and with consistent C.sup.13 NMR
spectral data. TLC (1:1) ethyl acetatehexane, Rf=0.44, PMA.
Microanalysis is Calc'd for C.sub.5 H.sub.9 O.sub.3 Br: C, 30.48; H, 4.60;
Br, 40.56
Found: C, 29.76; H, 4.50; Br, 39.86.
(d) Methyl 3S-((t-butyl)diphenylsilyloxy)-4-bromo butanoate
##STR44##
A solution of (S)-4-bromo-3-hydroxybutanoic acid, methyl ester obtained in
step (c) above (4.0 g, 20.4 mmole), imidazole (6.94 g, 5.0 eq.), and
4-dimethylamino pyridine (4-DMAP) (12 mg, 0.005 eq.) in dry
dimethylformamide (DMF) (40 ml) was treated with t-butyldiphenylsilyl
chloride (5.84 ml, 1.1 eq.) and the homogeneous mixture stirred overnight
under argon at room temperature. The mixture was partitioned between 5%
KHSO.sub.4 and ethyl acetate, the organic phase washed with H.sub.2 O and
brine then dried over anhydrous Na.sub.2 SO.sub.4 and evaporated to give
9.32 g (100%) of the title compound as a clear, viscous oil with
consistent C.sup.13 NMR spectral data. TLC (3:1) hexane-ethyl acetate,
product. Rf silyl ether=0.75, U. V. and PMA.
(e) Methyl 3S-((t-butyl)diphenylsilyloxy)4-iodo butanoate
##STR45##
A solution of the crude methyl 3S-((t-butyl)-diphenylsilyloxy)-4-bromo
butanoate obtained in step (d) above (9.32 g, 201 mmole) in methyl ethyl
ketone (60 ml, over 4.ANG. sieves) was treated with sodium iodide (15.06
g, 100.5 mmole, 5.0 eq.) and the yellow suspension refluxed for 5.0 hours
under argon. The mixture was cooled, diluted with ethyl acetate, filtered,
the filtrate washed with dilute NaHSO.sub.3 (until colorless) and brine,
then dried over anhydrous Na.sub.2 SO.sub.4 and evaporated in vacuo to
give 10.17 g of a yellow oil. The crude oil was purified by flash
chromatography on Merck silica gel (600 g, 50:1) eluting with (3:1)
hexane-CH.sub.2 Cl.sub.2. Product fractions were evaporated to give 7.691
g (74.2%, combined yield for both steps) of the title compound as a clear,
colorless, viscous oil with consistent C.sup.13 NMR spectral data and
H.sup.1 NMR spectral data. TLC (3:1) hexane-ethyl acetate, product.
Rf=0.75, U.V. and PMA. (Product co-spots with starting material).
(f) Methyl 3S-t-butyldiphenylsilyloxy-4-thiotosylate butanoate
##STR46##
A reaction mixture containing potassium thiotosylate (2.2 g, 10 mM), and
methyl 3S-((t-butyl)diphenylsilyloxy)-4-iodo butanoate obtained in step
(e) above (4.9 g, 10 mM) in dimethylformamide (25 ml) was stirred at room
temperature for 3 days and heated at 50.degree. C. for 24 hours until thin
layer chromatography (TLC) indicated an absence of starting material. The
reaction mixture was diluted with ethyl acetate (EtOAc) (200 ml), washed
2.times.saturated NaHCO.sub.3, 1.times.H.sub.2 O, 1.times.saturated NaCl,
dried (Na.sub.2 SO.sub.4) and concentrated under reduced pressure. The
oily residue was purified by flash chromatography (Merck Silica gel, 10%
EtOAc/Hexane), yielding the pure title product as a colorless oil (5.32 g,
98.0%).
Anal. Calc'd for C.sub.28 H.sub.24 S.sub.2 SiO.sub.5
Calc'd C,61.96; H,6.31; S, 11.81;
Found C,61.71; H,6.37; S, 11.64.
(g) 2,4-Dimethyl-N-phenylbenzenemethanimine
##STR47##
A solution of freshly distilled 2,4-dimethylbenzaldehyde (6.97 ml, 50
mmole) and distilled aniline (4.56 ml, 50 mmole) in dry toluene (80.0 ml)
was refluxed for 3.0 hours under argon in a flask equipped with a
Dean-Stark apparatus. The mixture was cooled, then evaporated in vacuo to
a yellow oil. The crude oil was purified by Kugelrohr distillation (0.5 mm
Hg, 160.degree.-180.degree. C.) to give 8.172 g (78.1%) of the title
benzeneimine as a light yellow oil which crystalized on standing to a low
melting solid. H.sup.1 NMR was consistent for the title product. TLC (4:1)
Hexane-Acetone, Rf=0.67 and 0.77 (geometric isomers), U.V. and I.sub.2.
(h) 2,4-Dimethyl-N-phenylbenzenemethanimine, dipalladium acetate complex
##STR48##
A mixture of the benzeneimine prepared in step (g) above (6.0 g, 28.6
mmole) in glacial acetic acid (144 ml) was treated with
palladium(II)acetate (6.44 g, 28.7 mmole) and the clear, red homogeneous
solution refluxed under argon for one hour. The resulting turbid mixture
was filtered warm through a packed 1/2" bed of Celite into 900 ml of
H.sub.2 O. Precipitated orange solid was collected by filtration and dried
in vacuo at 65.degree. C. over P.sub.2 O.sub.5 for 16.0 hours to give
10.627 g (85.5%) of the title palladium complex as an orange solid with
m.p.=194.degree.-196.degree. C. (Literature m.p. of a recrystallized
analytical sample=203.degree.-205.degree. C.).
(i) 4'-Fluoro-3,3', 5-trimethyl-2-formyl-1,1'-biphenyl
##STR49##
A Grignard reagent having the structure:
##STR50##
was prepared by adding 5-bromo-2-fluorotoluene (22.5 g, 60.9 mmole)
portionwise (enough to keep the (C.sub.2 H.sub.5).sub.2 O continually
refluxing) to stirred magnesium turnings (1.35 g, 55.4 mmole, 8.0 eq.) in
dry (C.sub.2 H.sub.5).sub.2 O (70.0 ml). The reaction was initiated in an
ultrasound device. After bromide addition was complete, the mixture was
stirred for one hour under argon at room temperature, then refluxed for 15
minutes and finally cooled back to room temperature.
In a second flask, a mixture of the dipalladium complex obtained in step
(h) above (3.0 g, 6.92 mmole) and triphenylphosphine (14.52 g, 55.4 mmole,
8.0 eq.) in dry benzene (100 ml) was stirred at room temperature under
argon for 30.0 minutes. The freshly prepared and filtered (glass wool
plug) Grignard reagent was then added in one portion by means of a cannula
to this solution and the mixture was stirred for 1.5 hours at room
temperature under argon. 6.0N HCl (35 ml) was added, the mixture stirred
an additional hour at room temperature, then filtered through packed
Celite (1/2" bed). The filtrate was diluted with (C.sub.2 H.sub.5).sub.2 O
(250 ml), washed with brine (2.times.100 ml), dried over anhydrous
MgSO.sub.4 and evaporated in vacuo to give 13.35 g of a viscous orange oil
which crystallized on standing. The crude orange solid was purified by
flash chromatography on Merck silica gel (700 g) eluting with neat hexane,
followed by (95:5) hexane-(C.sub.2 H.sub.5).sub.2 O. Product fractions
were evaporated to give 1.507 g (89.9%) of the title aldehyde as a light
yellow solid with m.p.=72.degree.-75.degree. C. (Literature reports
m.p.=73.degree.-74.degree. C.).
TLC: (95:5) hexane-(C.sub.2 H.sub.5).sub.2 O, Rf=0.40, U.V. and PMA.
(j) 4'-Fluoro-3,3',5-trimethyl-2-(2,2-dibromovinyl)-1,1'-biphenyl
##STR51##
A cooled (-10.degree. C., salt/ice bath) solution of the biphenyl aldehyde
prepared in step (i) above (242 mg, 1.0 mmole) and triphenylphosphine (787
mg, 3.0 mmole, 3.0 eq) in dry CH.sub.2 Cl.sub.2 (10 ml) was treated
dropwise with a CBr.sub.4 solution (497 mg, 1.5 mmole, 1.5 eq in CH.sub.2
Cl.sub.2 (5.0 ml)) over a 5 minute period. After 30 minutes at 0.degree.
C. the red-orange solution was partitioned between CH.sub.2 Cl.sub.2 and
saturated NaHCO.sub.3. The organic phase was washed with saturated
NaHCO.sub.3 and brine, then dried over anhydrous Na.sub.2 SO.sub.4 and
evaporated to give 1.478 g of a light brown solid. The crude solid was
purified by flash chromatography on LPS-1 silica gel (50:1) eluting with
(9:1) hexane-CH.sub.2 Cl.sub.2. Product fractions were evaporated to give
392 mg (99%) of the pure vinyl dibromide title product as a pale yellow
oil with consistent .sup.1 H-NMR and .sup.13 C-NMR spectral data. TLC
(95:5) hexane-ethyl acetate, Rf=0.51, UV and PMA. Mass spec, M+H=399
observed.
(k) 4'-Fluoro-3,3',5-trimethyl-2-ethynyl-1,1'-biphenyl
##STR52##
A -78.degree. C. (dry ice/acetone) solution of the vinyl dibromide prepared
in step (J) above (336 mg, 0.844 mmole) in dry tetrahydrofuran (5 ml) was
treated dropwise via syringe with a 1.6M solution of n-butyl lithium
(n-BuLi) in hexanes (1.06 ml, 1.7 mmole, 2.0 eq) and the mixture stirred
at -78.degree. C. under argon for one hour. During the n-BuLi addition
color changes from colorless to deep yellow to pale yellow to deep-blue
purple were evident. The mixture was quenched at -78.degree. C. by the
dropwise addition of saturated NH.sub.4 Cl (4 ml), allowed to warm to room
temperature, extracted with (C.sub.2 H.sub.5).sub.2 O, the ethereal layer
washed with brine, dried over anhydrous MgSO.sub.4 and evaporated to give
191 mg of a green oil. The crude oil was purified by flash chromatography
on LPS-1 silica gel (60:1) eluting with neat hexanes. Product fractions
were evaporated to give 185 mg (92%) of the title acetylene product as a
clear oil which eventually turned deep blue on standing at -20.degree. C.
under argon. .sup.1 H-NMR and .sup.13 C-NMR were consistent for the title
product. TLC neat hexane, Rf=0.18 UV (bright purple) and PMA. Mass Spec.
M+H=239 observed.
(1)
(S)-4-[[[4'-Fluoro-3,3',5-trimethyl-[1,1'-biphenyl]-2-yl]ethynyl]thio]-3-(
t-butyldiphenylsilyloxy)butanoic acid, methyl ester
##STR53##
A -78.degree. C. solution of the acetylene compound prepared in step (k)
above (1.10 g, 4.65 mM) in dry tetrahydrofuran (20 ml) was treated
dropwise with a 2.5M solution of n-butyl lithium in hexanes (1.86 ml, 4.65
mM, 1.0 eq). The mixture was stirred under argon for 30 minutes and then
transferred via canula to a -78.degree. C. solution of methyl
3S-t-butyldiphenylsilyloxy-4-thiotosylate butanoate prepared in step (f)
above in dry tetrahydrofuran (20 ml). The clear pale yellow reaction
mixture was stirred at -78.degree. C. for 2 hours and then slowly warmed
to room temperature. The reaction mixture was quenched with saturated
NH.sub.4 Cl, and extracted with ether. The ethereal layer was washed with
saturated NaHCO.sub.3 and brine, then dried over anhydrous MgSO.sub.4 and
evaporated to a brown oily residue. Purification by flash chromatography
(Merck Silica gel, 3% ethyl acetate/hexane) afforded the title product as
a colorless oil (2.42 g, 83.7%).
(m)
(S)-4-[[[4'-Fluoro-3,3',5-trimethyl[1,1'-biphenyl]-2-yl]ethynyl]thio]-3-hy
droxybutanoic acid, methyl ester
##STR54##
A solution of
(S)-4-[[[4'-fluoro-3,3',5-trimethyl[1,1'-biphenyl]-2-yl]ethynyl]thio]-3-(t
-butyldiphenylsilyloxy)butanoic acid, methyl ester (1.2 g, 1.9 mM) in dry
tetrahydrofuran (10 ml) was treated with glacial acetic acid (0.43 ml,
7.70 mM, 4.0 eq) followed by a 1.0M tetrabutylammonium fluoride solution
in tetrahydrofuran (5.78 ml, 5.78 mM, 3.0 eq) and the dark reaction
mixture stirred overnight at room temperature under argon. The mixture was
diluted with 10 ml of ice water and extracted with ethyl acetate
(2.times.). The organic phase was washed with saturated NaHCO.sub.3 and
brine, then dried over anhydrous Na.sub.2 SO.sub.4 and evaporated to give
a dark oily residue. The crude oil was purified by flash chromatography
(Merck Silica gel, 20% ethyl acetate/hexane) affording the title compound
as a dark oil (0.53 g, 71.6%).
EXAMPLE 2
Preparation of
(S)-4-[[[4'-Fluoro-3,3',5-trimethyl[1,1'-biphenyl]-2-yl]ethynyl]thio]-3-hy
droxybutanoic acid, monosodium salt
##STR55##
A solution of (S)-4-[[[4'-fluoro-3,3',
5-trimethyl[1,1'-biphenyl]-2-yl]ethynyl]thio]-3-hydroxybutanoic acid,
methyl ester obtained in Example 1 above (0.15 g, 0.39 mM) in
methanol/H.sub.2 O (3/1) was treated with 1N NaOH (1.16 ml, 1.16 mM, 3 eq)
and stirred at room temperature for 1 hour (TLC indicated the absence of
starting material). The reaction mixture was concentrated and the residue
dissolved in a minimum amount of water and chromatographed on HP-20 resin
eluting with H.sub.2 O until neutral fractions were obtained, followed by
25% methanol/H.sub.2 O, 50% methanol/H.sub.2 O and 75% methanol/H.sub.2 O.
Collected product fractions were evaporated, dissolved in H.sub.2 O,
filtered, frozen and lyophilized to a white lyophilate as the title
compound sodium salt (115 mg, 86.0%).
R.sub.f =0.24 (EM Silica gel) 20% CH.sub.3 OH/CHCl.sub.3, UV,I.sub.2 UV
.lambda. max (.epsilon.)=240 (26,020), 207 nm (30,840) Anal. Calc'd for
C.sub.21 H.sub.20 FO.sub.3 SNa.times.0.66 H.sub.2 O. Calc'd C,62.09;
H,5.29; F,4.68; S,7.89. Found C,62.11; H,5.08; F,4.78; S,7.70.
EXAMPLE 3
Preparation of
(S)-4-[[[4'-Fluoro-3,3',5-trimethyl[1,1'-biphenyl]-2-yl]ethynyl]sulfinyl]-
3-hydroxy-butanoic acid, monosodium salt
##STR56##
A solution of
(S)-4-[[[4'-fluoro-3,3',5-trimethyl[1,1'-biphenyl]-2-yl]ethynyl]thio]-3-hy
droxybutanoic acid, monosodium salt (175 mg, 0.44 mM) prepared as in
Example 2 above and sodium metaperiodate (0.56 g, 2.64 mM) in CH.sub.3
OH/H.sub.2 O (6 ml, 1/1) was stirred under argon for 24 hours. (TLC
indicated the absence of starting material). The reaction mixture was
concentrated, the residue dissolved in a minimum amount of water and
chromatographed on HP-20 resin eluting with H.sub.2 O, followed by 25%
CH.sub.3 OH/H.sub.2 O, 50CH.sub.3 OH/H.sub.2 O and 75% CH.sub.3 OH/H.sub.2
O. Collected product fractions were evaporated, dissolved in H.sub.2 O (50
ml), filtered, frozen and lyophilized to a white electrostatic lyophilate
as the title compound sodium salt (133 mg, 73.8 %) (mixture of sulfoxide
isomers). R.sub.f =0.40 (EM Silica gel) 30% CH.sub.3 OH/CHCl.sub.3,
UV,I.sub.2 UV .lambda. max (.epsilon.)=273 (14,300), 238 (27,800), 209 nm
(33,300)
Anal. Calc'd for C.sub.21 H.sub.20 FO.sub.4 SNa.times.2.40 H.sub.2 O.
Calc'd C,55.60; H,5.51; F,4.19; S,7.07.
Found C,55.16; H,5.03; F,3.99; S,6.61.
EXAMPLE 4
Preparation of
(S)-4-[[[4'-Fluoro-3,3',5-trimethyl[1,1'-biphenyl]-2-yl]ethynyl]sulfonyl]-
3-hydroxybutanoic acid, monosodium salt
##STR57##
A reaction mixture containing
(S)-4-[[[4'-fluoro-3,3',5-trimethyl[1,1'-biphenyl]-2-yl]-ethynyl]thio]-3-h
ydroxybutanoic acid, monosodium salt prepared in Example 2 above (0.17 g,
0.43 mM) and m-chloroperoxybenzoic acid (0.178 g, 0.86 mM, 80-85%) in
CHCl.sub.3 (10 ml) was stirred at room temperature for 24 hours (TLC
indicated the absence of starting material). The reaction mixture was
concentrated, the residue dissolved in water and chromatographed on HP-20
resin eluting with H.sub.2 O, followed by 25% CH.sub.3 OH/H.sub.2 O, 50%
CH.sub.3 OH/H.sub.2 O and 75% CH.sub.3 OH/H.sub.2 O. Collected product
fractions were evaporated, dissolved in H.sub.2 O (100 ml, milky
solution), frozen and lyophilized to an off-white residue, which was
triturated with hexane yielding off-white hard solids of the title
product, (0.15 g, 55.5%)
R.sub.f =0.50 (EM Silica gel) 30% CH.sub.3 OH/CHCl.sub.3, UV,I.sub.2 UV
.lambda. max (.epsilon.)=274 (13,800), 236 (16,500), 205 nm (35,900)
Anal. Calc'd for C.sub.21 H.sub.20 FO.sub.5 SNa.times.0.25 C.sub.6
H.sub.14.
Calc'd C,60.33; H,5.29; F,4.24; S,7.16.
Found C,60.54; H,5.00; F,4.07; S,7.35.
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